Establishment of Drug-resistant Cell Lines as a Model in Experimental Oncology: A Review.

Anticancer Res. 2019 Dec;39(12):6443-6455

Authors: Amaral MVS, DE Sousa Portilho AJ, DA Silva EL, DE Oliveira Sales L, DA Silva Maués JH, DE Moraes MEA, Moreira-Nunes CA

Abstract
Many types of cancer are initially susceptible to chemotherapy, but during treatment, patients may develop resistance to therapy. Knowing that acquisition of drug resistance is a major clinical problem in antineoplastic treatment, the present work aimed to present, through a literature review, the development of chemoresistant cells lines as a model in experimental oncology. A total of 110 drug-resistant cell lines, mainly from lung tumors and leukemias, have been developed. In addition, it has been observed that the drugs used for induction of resistance represented the drugs used for first-line treatment of each neoplasia, since the ideal chemotherapeutic treatment to induce resistance in vitro aims at a better modulation of the therapeutic response in order to better study the mechanisms of resistance.

PMID: 31810908 [PubMed - in process]

Pragmatic Trials in Genomic Medicine: The Integrating Pharmacogenetics in Clinical Care (I-PICC) Study.

Clin Transl Sci. 2019 Dec 06;:

Authors: Brunette CA, Miller SJ, Majahalme N, Hau C, MacMullen L, Advani S, Ludin SA, Zimolzak AJ, Vassy JL

Abstract
Pragmatic clinical trials (PCTs) have an established presence in clinical research and yet have only recently garnered attention within the landscape of genomic medicine. Using the PRagmatic-Explanatory Continuum Indicator Summary 2 (PRECIS-2) as a framework, this article illustrates the application of PCT principles to The Integrating Pharmacogenetics In Clinical Care (I-PICC) Study, a trial of pharmacogenetic testing prior to statin initiation for cardiovascular disease prevention in primary care. The trial achieved high engagement with providers (85% enrolled of those approached) and enrolled a representative sample of participants for which statin therapy would be recommended. The I-PICC Study has a high level of pragmatism, which should enhance the generalizability of its findings. The PRECIS-2 may be useful in the design and evaluation of PCTs of genomic medicine interventions, contributing to the generation of evidence that can bridge the gap between genomics innovation and clinical adoption.

PMID: 31808996 [PubMed - as supplied by publisher]

Associations between Prediagnostic Concentrations of Circulating Sex Steroid Hormones and Liver Cancer Among Post-Menopausal Women.

Hepatology. 2019 Dec 05;:

Authors: Petrick JL, Florio AA, Zhang X, Zeleniuch-Jacquotte A, Wactawski-Wende J, Van Den Eeden SK, Stanczyk FZ, Simon TG, Sinha R, Sesso HD, Schairer C, Rosenberg L, Rohan TE, Purdue MP, Palmer JR, Linet MS, Liao LM, Lee IM, Koshiol J, Kitahara CM, Kirsh VA, Hofmann JN, Guillemette C, Graubard BI, Giovannucci E, Gaziano JM, Gapster SM, Freedman ND, Engel LS, Chong DQ, Chen Y, Chan AT, Caron P, Buring JE, Bradwin G, Beane Freeman LE, Campbell PT, McGlynn KA

Abstract
BACKGROUND: In almost all countries, incidence rates of liver cancer are 100-200% higher in males than in females. However, this difference is predominantly driven by hepatocellular carcinoma (HCC), which accounts for 75% of liver cancer cases. Intrahepatic cholangiocarcinoma (ICC) accounts for 12% of cases and has rates only 30% higher in males. Hormones are hypothesized to underlie observed sex differences. We investigated whether prediagnostic circulating hormone and sex hormone binding globulin (SHBG) levels were associated with liver cancer risk, overall and by histology, by leveraging resources from five prospective cohorts.
METHODS: Seven sex steroid hormones and SHBG were quantitated using gas chromatography-tandem mass spectrometry (GC-MS/MS) and competitive electrochemiluminescence immunoassay, respectively, from baseline serum/plasma samples of 191 post-menopausal female liver cancer cases (HCC n=83, ICC n=56) and 426 controls, matched on sex, cohort, age, race/ethnicity, and blood collection date. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between a one-unit increase in log2 hormone value (approximate doubling of circulating concentration) and liver cancer were calculated using multivariable-adjusted conditional logistic regression.
RESULTS: A doubling in the concentration of 4-androstenedione was associated with a 50% decreased liver cancer risk (OR=0.50,95%CI=0.30-0.82), while SHBG was associated with a 31% increased risk (OR=1.31,95%CI=1.05-1.63). Examining histology, a doubling of estradiol was associated with a 40% increased risk of ICC (OR=1.40,95%CI=1.05-1.89), but not HCC (OR=1.12,95%CI=0.81-1.54).
CONCLUSIONS: This study provides the first evidence that higher levels of 4-androstenedione may be associated with lower, and SHBG with higher, liver cancer risk in women. However, this study does not support the hypothesis that higher estrogen levels decrease liver cancer risk. Indeed, estradiol may be associated with an increased ICC risk.

PMID: 31808181 [PubMed - as supplied by publisher]

Pharmacogenomics In Pharmacy Practice: Current Perspectives.

Integr Pharm Res Pract. 2019;8:97-104

Authors: Elewa H, Awaisu A

Abstract
Pharmacogenomics (i.e., the application of genetic information in predicting an individual's response to drug therapy) plays an increasingly important role in drug development and decision-making regarding precision medicine. This has been shown to reduce the risk of adverse events and improve patient health-care outcomes through targeted therapies and dosing. As the field of pharmacogenomics rapidly evolves, the role of pharmacists in the education, implementation, and research applications of pharmacogenomics is becoming increasingly recognized. This paper aims to provide an overview and current perspectives of pharmacogenomics in contemporary clinical pharmacy practice and to discuss the future directions on advancing pharmacogenomics education, application, and research in pharmacy practice.

PMID: 31807435 [PubMed]

Antihypertensive Effect Of Amlodipine In Co-Administration With Omeprazole In Patients With Hypertension And Acid-Related Disorders: Cytochrome P450-Associated Aspects.

Pharmgenomics Pers Med. 2019;12:329-339

Authors: Dorofeeva MN, Shikh EV, Sizova ZM, Tarasenko AV, Denisenko NP, Smirnov VV, Ryzhikova KA, Sozaeva ZA, Grishina EA, Sychev DA

Abstract
Background: CYP2C19 and CYP3A are the main enzymes involved in omeprazole metabolism, while CYP3A is the principal enzyme family for amlodipine biotransformation. Concomitant use of these drugs in patients with hypertension and acid-related disorders (ARD) might lead to drug-drug interaction.
Purpose: The aim of the study was to find if adding omeprazole for treating ARD to amlodipine long-term therapy of hypertension influenced blood pressure of CYP2C19 polymorphism carriers.
Patients and methods: Fifty-one patients diagnosed with hypertension and ARD were enrolled in the study. Evaluation of antihypertensive therapy was performed by office (OBPM) and ambulatory (ABPM) blood pressure monitoring. Peripheral venous blood was collected for DNA extraction and real-time polymerase chain reaction was performed for CYP2C19*2G681A (rs4244285), CYP2C19*3G636A (rs4986893) and CYP2C19*17C-806T (rs12248560) polymorphisms analysis.
Results: Of 51 patients there were 21 extensive metabolizers (EMs), 18 ultrarapid metabolizers (UMs) and 12 intermediate metabolizers (IMs). The results of OBPM showed that antihypertensive effect was significantly more pronounced in IMs compared to EMs or UMs and the average group value in the following parameters: average office systolic blood pressure (BP), dynamics of the average office systolic BP. According to dynamics of diastolic BP, the antihypertensive effect was also significantly higher in IMs than in UMs and the average group value. The results of ABPM revealed that there was a significantly more pronounced antihypertensive effect in IMs compared to all other analyzed groups according to the dynamics of both daytime systolic and 24 hr diastolic BP. The average daytime diastolic BP and its dynamics, the average 24 hr systolic BP and its dynamics were higher in IMs compared to EMs and UMs.
Conclusion: Adding omeprazole to long-term amlodipine therapy in patients with hypertension and ARD may lead to a significantly more pronounced antihypertensive effect in patients genotyped CYP2C19 IMs.

PMID: 31807051 [PubMed]

A Cross-Sectional Study Assessing Appropriateness Of Inhaled Corticosteroid Treatment In Primary And Secondary Care Patients With COPD In Sweden.

Int J Chron Obstruct Pulmon Dis. 2019;14:2451-2460

Authors: Sulku J, Janson C, Melhus H, Malinovschi A, Ställberg B, Bröms K, Högman M, Lisspers K, Hammarlund-Udenaes M, Nielsen EI

Abstract
Purpose: Inhaled corticosteroids (ICS) are often more widely prescribed in the treatment of chronic obstructive pulmonary disease (COPD) than what is recommended in the guidelines. The aim of this study was to evaluate the appropriateness of ICS treatment in COPD patients using the algorithm proposed by the International Primary Care Respiratory Group (IPCRG) and to identify factors associated with ICS treatment.
Patients and methods: Appropriateness of ICS therapy was studied with respect to concomitant asthma, history of exacerbations and blood eosinophils (B-Eos) in a Swedish cohort of primary and secondary care patients with COPD. Factors associated with ICS were investigated using multivariable logistic regression.
Results: Triple treatment was found to be the most common treatment combination, used by 46% of the 561 included patients, and in total 63% were using ICS. When applying the IPCRG algorithm, there was a possible indication for discontinuation of ICS in 55% of the patients with ICS treatment. Of the patients not using ICS, 18% had an indication for starting such treatment. The strongest factors associated with ICS therapy were frequent exacerbations (aOR 8.61, 95% CI 4.06, 20.67), secondary care contacts (aOR 6.99, 95% CI 2.48, 25.28) and very severe airflow limitation (aOR 5.91, 95% CI 1.53, 26.58).
Conclusion: More than half of the COPD patients on ICS met the criteria where withdrawal of the treatment could be tried. There was, however, also a subgroup of patients not using ICS for whom there was an indication for starting ICS treatment. Patients using ICS were characterized by more frequent exacerbations and lower lung function.

PMID: 31806954 [PubMed - in process]

Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.

Pharmacogenomics J. 2019 Dec 06;:

Authors: de Las Fuentes L, Sung YJ, Sitlani CM, Avery CL, Bartz TM, Keyser C, Evans DS, Li X, Musani SK, Ruiter R, Smith AV, Sun F, Trompet S, Xu H, Arnett DK, Bis JC, Broeckel U, Busch EL, Chen YI, Correa A, Cummings SR, Floyd JS, Ford I, Guo X, Harris TB, Ikram MA, Lange L, Launer LJ, Reiner AP, Schwander K, Smith NL, Sotoodehnia N, Stewart JD, Stott DJ, Stürmer T, Taylor KD, Uitterlinden A, Vasan RS, Wiggins KL, Cupples LA, Gudnason V, Heckbert SR, Jukema JW, Liu Y, Psaty BM, Rao DC, Rotter JI, Stricker B, Wilson JG, Whitsel EA

Abstract
Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

PMID: 31806883 [PubMed - as supplied by publisher]

Genetic contribution to lipid target achievement with statin therapy: a prospective study.

Pharmacogenomics J. 2019 Dec 06;:

Authors: Ruiz-Iruela C, Candás-Estébanez B, Pintó-Sala X, Baena-Díez N, Caixàs-Pedragós A, Güell-Miró R, Navarro-Badal R, Calmarza P, Puzo-Foncilla JL, Alía-Ramos P, Padró-Miquel A

Abstract
Statin therapy response is highly variable. Variants of lipid metabolism genes and statin pharmacokinetic modulators could play a role, however, the impact of most of these variants remains unconfirmed. A prospective and multicenter study included 252 patients was carried out in order to assess, according to achievement of LDL-C or non-HDL-C therapeutic targets and quantitative changes in lipid profiles, the impact of CETP, ABCA1, CYP2D6, and CYP2C9 gene candidate variants on the simvastatin, atorvastatin, and rosuvastatin response. Patients carrier ABCA1 rs2230806 and CYP2D6*3 variants are less likely to achieve therapeutic lipid targets (p = 0.020, OR = 0.59 [0.37, 0.93]; p = 0.040, OR = 0.23 [0.05, 0.93], respectively). Among CETP variants, rs708272 was linked to a 10.56% smaller reduction in LDL-C with rosuvastatin (95% CI = [1.27, 19.86] %; p = 0.028). In contrast, carriers of rs5882 had a 13.33% greater reduction in LDL-C (95% CI = [25.38, 1.28]; p = 0.032). If these findings are confirmed, ABCA1, CYP2D6, and CETP genotyping could be used to help predict which statin and dosage is appropriate in order to improve personalized medicine.

PMID: 31806882 [PubMed - as supplied by publisher]

OPRM1, OPRK1, and COMT genetic polymorphisms associated with opioid effects on experimental pain: a randomized, double-blind, placebo-controlled study.

Pharmacogenomics J. 2019 Dec 06;:

Authors: Ho KWD, Wallace MR, Staud R, Fillingim RB

Abstract
Genetic polymorphisms have been shown to affect opioid requirement for pain relief. However, true genetic effect is often difficult to assess due to underlying pain conditions and placebo effects. The goal of this study was to understand how common polymorphisms affect opioid effects while controlling for these factors. A randomized, double-blind, placebo-controlled study was implemented to assess how opioid effects are modulated by COMT (rs6269, rs4633, rs4848, rs4680), OPRM1 (A118G), and OPRK1 (rs1051660, rs702764, rs16918875). One hundred and eight healthy subjects underwent experimental pain testing before and after morphine, butorphanol, and placebo (saline). Association analysis was performed between polymorphisms/haplotypes and opioid response, while correcting for race, gender, placebo effects, and multiple comparisons. Pressure pain was significantly associated with rs6269 and rs4633 following butorphanol. The AA genotype of rs4680 or A_T_C_A/ A_T_C_A (rs6269_rs4633_ rs4818_rs4680) diplotype of COMT, combined with the AG genotype of OPRM1 A118G, showed significantly increased pressure pain threshold from butorphanol. Opioid effects on pressure, ischemic, heat pain, and side effects were nominally associated with several SNPs and haplotypes. Effects were often present in one opioid but not the other. This indicates that these polymorphisms affect pain relief from opioids, and that their effects are opioid and pain modality specific.

PMID: 31806881 [PubMed - as supplied by publisher]

Drug-induced pancreatitis: An update.

Arab J Gastroenterol. 2019 Dec 02;:

Authors: Zheng J, Yang QJ, Dang FT, Yang J

Abstract
Drug-induced pancreatitis is a disease that is receiving increasing attention. This article reviews the advances in the incidence, risk factors, pathogenesis, diagnosis, treatment and prevention of drug-induced pancreatitis by reviewing the literature on drug-induced pancreatitis, especially in the literature of the latest 10 years. The incidence of drug-induced pancreatitis is relatively low, however, there is an increasing trend with the widespread use of drugs, and the incidence seems to be related to regional distribution. There is currently lack of data on the epidemiology of drug-induced pancreatitis in China. In recent years, research on the pathogenesis of drug-induced pancreatitis has made some progress, but further research is needed. Drug-induced pancreatitis is a diagnosis of exclusion. With the deepening of understanding and research, a new diagnostic process has been proposed. Pharmacogenomics is expected to help prevent and perform an individual treatment of drug-induced pancreatitis.

PMID: 31806409 [PubMed - as supplied by publisher]

RNA-seq analysis of testes from flurochloridone-treated rats.

Toxicol Mech Methods. 2019 Dec 05;:1-18

Authors: Zhou S, Li R, Hou W, Wang Y, Zhang S, Yu Y, Zhang L, Zhu H, Zhang Z, Fang J, Chang X, Zhang Y, Liu L, Tang L, Zhou Z

Abstract
Flurochloridone (FLC) is a widely used herbicide in developing countries. Although the testes are a target organ for FLC in rats, the adverse effects of FLC on testes have not been fully elucidated. To clarify them, we performed RNA-seq analysis using the testes of FLC-treated rats from our previous subchronic toxicity tests. Unilateral testes of three male rats from solvent control groupand three FLC-treated groups (3 mg/kg, 31.25 mg/kg and 125 mg/kg) were used for RNA extraction. A poly A selection protocol coupled with an Illumina TruSeq RNA-Seq library protocol was used to construct RNA-Seq libraries. Principal component analysis (PCA), differentially expressed gene (DEG) analysis, and hierarchical clustering analysis (HCA) were conducted using R. Gene Ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to understand the biological characteristics of the DEGs using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The results indicated that many up-regulated DEGs were enriched in pathways associated with testicular injury, such as mitogen-activated protein kinase (MAPK) signaling, lysosome and focal adhesion. Many down-regulated DEGs were enriched in pathways associated with testicular reproduction function, such as sexual reproduction, spermatogenesis and germ cell development. Moreover, we confirmed the oral no-observed-adverse-effect level (NOAEL) of 3 mg/kg in subchronic toxicity test, because the overall testicular gene expression in 3 mg/kg FLC-treated group was similar to that of the solvent control group. In 31.25 mg/kg and 125 mg/kg groups, DEGs revealed that testicular injury was related to oxidative stress.

PMID: 31805805 [PubMed - as supplied by publisher]

Response to Letter: Cost Implications of Reactive Versus Prospective Testing for Dihydropyrimidine Dehydrogenase Deficiency in Patients With Colorectal Cancer: A Single-Institution Experience.

Dose Response. 2019 Oct-Dec;17(4):1559325819887068

Authors: O'Farrell E, Bird B, Murphy C

PMID: 31802992 [PubMed]

Concepts Driving Pharmacogenomics Implementation Into Everyday Healthcare.

Pharmgenomics Pers Med. 2019;12:305-318

Authors: Giri J, Moyer AM, Bielinski SJ, Caraballo PJ

Abstract
Pharmacogenomics (PGx) is often promoted as the domain of precision medicine with the greatest potential to readily impact everyday healthcare. Rapid advances in PGx knowledge derived from extensive basic and clinical research along with decreasing costs of laboratory testing have led to an increased interest in PGx and expectations of imminent clinical translation with substantial clinical impact. However, the implementation of PGx into clinical workflows is neither simple nor straightforward, and comprehensive processes and multidisciplinary collaboration are required. Several national and international institutions have pioneered models for implementing clinical PGx, and these initial models have led to a better understanding of unresolved challenges. In this review, we have categorized and explored the most relevant of these challenges to highlight potential gaps and present possible solutions. We describe the ongoing need for basic and clinical research to drive further developments in evidence-based medicine. Integration into daily clinical workflows introduces new challenges requiring innovative solutions; specifically those related to the electronic health record and embedded clinical decision support. We describe advances in PGx testing and result reporting and describe the critical need for increased standardization in these areas across laboratories. We also explore the complexity of the PGx knowledge required for clinical practice and the need for educational strategies to ensure adequate understanding among members of current and future healthcare teams. Finally, we evaluate knowledge obtained from previous implementation efforts and discuss how to best apply these learnings to future projects. Despite these challenges, the future of precision medicine appears promising due to the rapidity of recent advances in the field and current multidisciplinary efforts to effectively translate PGx to everyday clinical practice.

PMID: 31802928 [PubMed]

Statin-induced LDL cholesterol response and type 2 diabetes: a bidirectional two-sample Mendelian randomization study.

Pharmacogenomics J. 2019 Dec 05;:

Authors: Smit RAJ, Trompet S, Leong A, Goodarzi MO, Postmus I, Warren H, Theusch E, Barnes MR, Arsenault BJ, Li X, Feng Q, Chasman DI, Cupples LA, Hitman GA, Krauss RM, Psaty BM, Rotter JI, Cessie SL, Stein CM, Jukema JW, GIST consortium

Abstract
It remains unclear whether the increased risk of new-onset type 2 diabetes (T2D) seen in statin users is due to low LDL-C concentrations, or due to the statin-induced proportional change in LDL-C. In addition, genetic instruments have not been proposed before to examine whether liability to T2D might cause greater proportional statin-induced LDL-C lowering. Using summary-level statistics from the Genomic Investigation of Statin Therapy (GIST, nmax = 40,914) and DIAGRAM (nmax = 159,208) consortia, we found a positive genetic correlation between LDL-C statin response and T2D using LD score regression (rgenetic = 0.36, s.e. = 0.13). However, mendelian randomization analyses did not provide support for statin response having a causal effect on T2D risk (OR 1.00 (95% CI: 0.97, 1.03) per 10% increase in statin response), nor that liability to T2D has a causal effect on statin-induced LDL-C response (0.20% increase in response (95% CI: -0.40, 0.80) per doubling of odds of liability to T2D). Although we found no evidence to suggest that proportional statin response influences T2D risk, a definitive assessment should be made in populations comprised exclusively of statin users, as the presence of nonstatin users in the DIAGRAM dataset may have substantially diluted our effect estimate.

PMID: 31801993 [PubMed - as supplied by publisher]

Prospective validation of the International Warfarin Pharmacogenetics Consortium algorithm in high-risk elderly people (VIALE study).

Pharmacogenomics J. 2019 Dec 05;:

Authors: Filippelli A, Signoriello S, Bancone C, Corbi G, Manzo V, Iesu S, Politi C, Gigantino A, De Donato MT, Masiello P, Simeon V, Della Corte A, Cellurale M, Conti V, Frigino M, Ciarambino T, Marracino M, Carpenito L, Ferrara N, De Feo M, Gallo C

Abstract
We assessed the predictive accuracy of the Warfarin Pharmacogenetics Consortium (IWPC) algorithm in a prospective cohort of 376 high-risk elderly patients (≥65 years) who required new treatment with warfarin for either medical (non valvular atrial fibrillation) or surgical conditions (heart valve replacement), had ≥1 comorbid conditions, and regularly used ≥2 other drugs. Follow-up visits were performed according to clinical practice and lasted for a maximum of 1 year. Two hundred and eighty-three (75%) patients achieved a stable maintenance dose. Warfarin maintenance doses were low on average (median 20.3 mg/week, interquartile range, 14.1-27.7 mg/week) and were substantially overestimated by the IWPC algorithm. Overall the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable dose was equal to 37.5%, (95% CI 32.0-43.3%). IWPC algorithm explained only 31% of the actual warfarin dose variability. Modifications of the IWPC algorithm are needed in high-risk elderly people.

PMID: 31801992 [PubMed - as supplied by publisher]

Whole Genome Expression Analyses of miRNAs and mRNAs Suggest the Involvement of miR-320a and miR-155-3p and their Targeted Genes in Lithium Response in Bipolar Disorder.

Int J Mol Sci. 2019 Nov 30;20(23):

Authors: Pisanu C, Merkouri Papadima E, Melis C, Congiu D, Loizedda A, Orrù N, Calza S, Orrù S, Carcassi C, Severino G, Ardau R, Chillotti C, Del Zompo M, Squassina A

Abstract
Lithium is the mainstay in the maintenance of bipolar disorder (BD) and the most efficacious pharmacological treatment in suicide prevention. Nevertheless, its use is hampered by a high interindividual variability and important side effects. Genetic and epigenetic factors have been suggested to modulate lithium response, but findings so far have not allowed identifying molecular targets with predictive value. In this study we used next generation sequencing to measure genome-wide miRNA expression in lymphoblastoid cell lines from BD patients excellent responders (ER, n = 12) and non-responders (NR, n = 12) to lithium. These data were integrated with microarray genome-wide expression data to identify pairs of miRNA/mRNA inversely and significantly correlated. Significant pairs were prioritized based on strength of association and in-silico miRNA target prediction analyses to select candidates for validation with qRT-PCR. Thirty-one miRNAs were differentially expressed in ER vs. NR and inversely correlated with 418 genes differentially expressed between the two groups. A total of 331 of these correlations were also predicted by in-silico algorithms. miR-320a and miR-155-3p, as well as three of their targeted genes (CAPNS1 (Calpain Small Subunit 1) and RGS16 (Regulator of G Protein Signaling 16) for miR-320, SP4 (Sp4 Transcription Factor) for miR-155-3p) were validated. These miRNAs and mRNAs were previously implicated in psychiatric disorders (miR-320a and SP4), key processes of the central nervous system (CAPNS1, RGS16, SP4) or pathways involved in mental illnesses (miR-155-3p). Using an integrated approach, we identified miRNAs and their targeted genes potentially involved in lithium response in BD.

PMID: 31801218 [PubMed - in process]

Pharmacogenomics in the clinic: genetic polymorphism contributing to venlafaxine-associated heart failure.

Pharmacogenomics. 2019 Nov;20(17):1175-1178

Authors: Singh H, DuBois B, Al-Jammali Z, Barrett T

PMID: 31799914 [PubMed - in process]

Hepatocyte gene expression and DNA methylation as ancestry-dependent mechanisms in African Americans.

NPJ Genom Med. 2019;4:29

Authors: Park CS, De T, Xu Y, Zhong Y, Smithberger E, Alarcon C, Gamazon ER, Perera MA

Abstract
African Americans (AAs) are an admixed population with widely varying proportion of West African ancestry (WAA). Here we report the correlation of WAA to gene expression and DNA methylation in AA-derived hepatocytes, a cell type important in disease and drug response. We perform mediation analysis to test whether methylation is a mediator of the effect of ancestry on expression. GTEx samples and a second cohort are used as validation. One hundred and thirty-one genes are associated with WAA (FDR < 0.10), 28 of which replicate and represent 220 GWAS phenotypes. Among PharmGKB pharmacogenes, VDR, PTGIS, ALDH1A1, CYP2C19, and P2RY1 nominally associate with WAA (p < 0.05). We find 1037 WAA-associated, differentially methylated regions (FDR < 0.05), with hypomethylated genes enriched in drug-response pathways. In conclusion, WAA contributes to variability in hepatocyte expression and DNA methylation with identified genes previously implicated for diseases disproportionately affecting AAs, including cardiovascular (PTGIS, PLAT) and renal (APOL1) disease, and drug response (CYP2C19).

PMID: 31798965 [PubMed]

Translational Bioinformatics: Biobanks in the Precision Medicine Era.

Pac Symp Biocomput. 2020;25:743-747

Authors: Ritchie MD, Moore JH, Kim JH

Abstract
Translational bioinformatics (TBI) is focused on the integration of biomedical data science and informatics. This combination is extremely powerful for scientific discovery as well as translation into clinical practice. Several topics where TBI research is at the leading edge are 1) the use of large-scale biobanks linked to electronic health records, 2) pharmacogenomics, and 3) artificial intelligence and machine learning. This perspective discusses these three topics and points to the important elements for driving precision medicine into the future.

PMID: 31797645 [PubMed - in process]

PGxMine: Text mining for curation of PharmGKB.

Pac Symp Biocomput. 2020;25:611-622

Authors: Lever J, Barbarino JM, Gong L, Huddart R, Sangkuhl K, Whaley R, Whirl-Carrillo M, Woon M, Klein TE, Altman RB

Abstract
Precision medicine tailors treatment to individuals personal data including differences in their genome. The Pharmacogenomics Knowledgebase (PharmGKB) provides highly curated information on the effect of genetic variation on drug response and side effects for a wide range of drugs. PharmGKB's scientific curators triage, review and annotate a large number of papers each year but the task is challenging. We present the PGxMine resource, a text-mined resource of pharmacogenomic associations from all accessible published literature to assist in the curation of PharmGKB. We developed a supervised machine learning pipeline to extract associations between a variant (DNA and protein changes, star alleles and dbSNP identifiers) and a chemical. PGxMine covers 452 chemicals and 2,426 variants and contains 19,930 mentions of pharmacogenomic associations across 7,170 papers. An evaluation by PharmGKB curators found that 57 of the top 100 associations not found in PharmGKB led to 83 curatable papers and a further 24 associations would likely lead to curatable papers through citations. The results can be viewed at https://pgxmine.pharmgkb.org/ and code can be downloaded at https://github.com/jakelever/pgxmine.

PMID: 31797632 [PubMed - in process]